Project summary ? Homeostatic regulation of NG2 cell dynamics NG2 cells represent a fourth major glial cell population in the mammalian central nervous system that is distinct from neural stem cells, mature oligodendrocytes, astrocytes, or microglia. They generate oligodendrocytes and hence are an important source of remyelinating cells. They respond robustly to changes in the density of oligodendrocyte lineage cells or myelin and restore the correct number of oligodendrocytes needed to make the correct amount of myelin in the neural network. They are highly integrated in the neural network and interact not only among the cells in the oligodendrocyte lineage but also with neurons and other glia. The proposed project will investigate the mechanism of feedback signaling that maintains homeostasis of oligodendrocytes and myelin. In Aim 1, we will test the hypothesis that microglia play a critical role in regulating NG2 cell density under normal physiological conditions, as well as during remyelination. In Aim 2, we will test the hypotheses that the Hippo signaling mediates NG2 cell density-dependent proliferation and that cell adhesion molecules and exosome signaling between myelin and NG2 cells provide feedback signaling to NG2 cells that regulates oligodendrocyte differentiation. These hypotheses are based on findings from both systems analyses and specific cellular studies. The outcome of the study will advance our knowledge by establishing fundamental new principles related to oligodendrocyte lineage cell intrinsic and extrinsic mechanisms of homeostatic regulation of oligodendrocytes and myelin in the context of other cellular constituents.